Four broad objectives, which all deal with aspects of acid-base homeostasis, are described in this proposal. 1. Regulation of Renal Ammonia Production. Issues that will be pursued include the mechanism by which acute pH changes alter NH3 production with specific emphasis in the role of a urinary inhibitory factor identified in my laboratory; the signal which results in the transition from an acute response to an adaptive change in NH3 metabolism to include an indepth analysis of chronic respiratory acidosis; and the link between gluconeogenesis and glutamine metabolism. Experimental technique employed will include the isolated perfused kidney, intact rats and isolated renal cortical mitochondria. 2. Interaction Between NH3 Production and K ion Homeostasis. The influence of K ion on NH3 metabolism on urinary K ion excretion will be examined with the isolated perfused rat kidney. This model will also be used to investigate the renal response to potassium deprivation. 3. Control of Urinary Acid Excretion. Utilizing the isolated perfused kidneys an approach has been developed to examine maximal transtubular H ion gradients and H ion secretory capacity of the rat distal nephron. This technology will be applied to a variety of experimental settings in order to characterize the response of the intrinsic distal nephron H ion transport mechanism. 4. Feedback Control of Acid Production. The mechanism whereby systemic acid-base homeostasis influences ketoacid production and the metabolic site for this effect will be examined employing acute and chronic acid-base manipulation in the intact rat with fasting ketogenesis. A model of acute lactic acidosis will be developed and the impact of acid-base homeostasis on lactic acid production examined.